SummaryThe synapse is a nanoscale machine, which transfers, integrates and stores information in brain circuits. Its function relies on multimolecular networks of interactions whose composition and dynamics shape synaptic transmission. A large body of evidence indicates that synapses specialized in humans. Human synapses are more densely distributed along dendrites and their period of maturation is protracted compared to rodent or non-human primate synapses. The rules governing their plasticity also differ from the other mammalian species studied so far. These traits contribute to the formation and function of complex circuits supporting human cognitive abilities. Yet, the underlying molecular mechanisms are not known. Here we will investigate the role of molecular pathways linked to human evolution in the regulation of synaptic development and plasticity. The proposed research takes advantage of my previous work on Slit-Robo Rho GTPAse-activating protein 2 (SRGAP2), one of the few genes specifically duplicated in humans, and the only one implicated at synapses so far. We will use the duplications of SRGAP2 as a thread to uncover i) fundamental mechanisms of synaptic development and plasticity, and ii) regulations specific to human synapses. To achieve our goals, we will employ a multi-disciplinary approach based on in vivo manipulations in intact mouse cortical circuits, mass spectrometry, live-cell single-molecule super-resolution microscopy, electrophysiology, and engineering of cortical neurons derived from human pluripotent stem cells. The combination of mouse and human models will allow us to establish a robust framework to bridge the gap in knowledge between cellular neurobiology and human brain evolution, and better understand synaptic dysfunctions in neurodevelopmental disorders.

The synapse is a nanoscale machine, which transfers, integrates and stores information in brain circuits. Its function relies on multimolecular networks of interactions whose composition and dynamics shape synaptic transmission. A large body of evidence indicates that synapses specialized in humans. Human synapses are more densely distributed along dendrites and their period of maturation is protracted compared to rodent or non-human primate synapses. The rules governing their plasticity also differ from the other mammalian species studied so far. These traits contribute to the formation and function of complex circuits supporting human cognitive abilities. Yet, the underlying molecular mechanisms are not known. Here we will investigate the role of molecular pathways linked to human evolution in the regulation of synaptic development and plasticity. The proposed research takes advantage of my previous work on Slit-Robo Rho GTPAse-activating protein 2 (SRGAP2), one of the few genes specifically duplicated in humans, and the only one implicated at synapses so far. We will use the duplications of SRGAP2 as a thread to uncover i) fundamental mechanisms of synaptic development and plasticity, and ii) regulations specific to human synapses. To achieve our goals, we will employ a multi-disciplinary approach based on in vivo manipulations in intact mouse cortical circuits, mass spectrometry, live-cell single-molecule super-resolution microscopy, electrophysiology, and engineering of cortical neurons derived from human pluripotent stem cells. The combination of mouse and human models will allow us to establish a robust framework to bridge the gap in knowledge between cellular neurobiology and human brain evolution, and better understand synaptic dysfunctions in neurodevelopmental disorders.

Max ERC Funding

1 500 000 €

Duration

Start date: 2019-06-01, End date: 2024-05-31

Project acronymVitASTEM

ProjectRegulation of Single Hematopoietic Stem Cells by Intake of Vitamin A

SummaryQuiescence preserves the self-renewal capacity and the long-term function of hematopoietic stem cells (HSCs). The regulators of this dormant state include intrinsic pathways and soluble components in the bone marrow niche. Dysregulation of this process is poorly defined and might cause aberrant hematopoiesis. In my previous work, we defined the molecular landscape of HSCs by applying state of the art DNA-methylome, RNA-seq and proteome analyses, and found vitamin A/retinoic acid (RA)-induced signaling predominantly enriched in HSCs (Cabezas-Wallscheid et al., Cell Stem Cell 2014). Intriguingly, we observed that mice fed with a vitamin A-free diet exhibited a robust loss of HSCs (Cabezas-Wallscheid et al., Cell 2017). Treatment of mice with a RA agonist preserved HSC quiescence in stress-activated conditions, indicating that the balance between HSC maintenance and differentiation is tightly regulated by vitamin A signaling.
However, we are only beginning to understand the mechanisms how vitamin A regulates HSC fate. Since treatment of vitamin A deficiency currently shows extremely low therapeutic success, novel insights into the role of HSCs in the development of the disease will be of enormous therapeutic value.

Quiescence preserves the self-renewal capacity and the long-term function of hematopoietic stem cells (HSCs). The regulators of this dormant state include intrinsic pathways and soluble components in the bone marrow niche. Dysregulation of this process is poorly defined and might cause aberrant hematopoiesis. In my previous work, we defined the molecular landscape of HSCs by applying state of the art DNA-methylome, RNA-seq and proteome analyses, and found vitamin A/retinoic acid (RA)-induced signaling predominantly enriched in HSCs (Cabezas-Wallscheid et al., Cell Stem Cell 2014). Intriguingly, we observed that mice fed with a vitamin A-free diet exhibited a robust loss of HSCs (Cabezas-Wallscheid et al., Cell 2017). Treatment of mice with a RA agonist preserved HSC quiescence in stress-activated conditions, indicating that the balance between HSC maintenance and differentiation is tightly regulated by vitamin A signaling.
However, we are only beginning to understand the mechanisms how vitamin A regulates HSC fate. Since treatment of vitamin A deficiency currently shows extremely low therapeutic success, novel insights into the role of HSCs in the development of the disease will be of enormous therapeutic value.